HU216841B - Process for the preparation of ketorolac-(2-pyrrolidinoethyl)-ester salts and pharmaceutical compositions containing them - Google Patents

Abstract

The present invention relates to a process for the preparation of pharmaceutically acceptable addition salts of (±) -5-benzoyl-2,3-dihydro-1H-pyrrolizine-1-carboxylic acid 2- (1-pyrrolidinyl) ethyl ester of formula (I). Alkylation of (±) -5-benzoyl-2,3-dihydro-1 H -pyrrolidine-1-carboxylic acid with 2- (1-pyrrolidinyl) ethyl chloride or equivalent alkylating agent is accomplished by acid addition of the appropriate acid to form the desired addition salt. The present invention also relates to a process for the preparation of a pharmaceutical composition containing such addition salts as an active ingredient. The compositions of the present invention are analgesic / anti-analgesic with no unwanted side effects. ŕ

Description

The present invention relates to the preparation of pharmaceutically acceptable addition salts of (±) -5-benzoyl-2,3-dihydro-1H-pyrrolizine-1-carboxylic acid 2- (pyrrolidinoylethyl) ester and pharmaceutical compositions containing them.

Non-steroidal analgesics / anti-inflammatory drugs are regularly used to treat chronic inflammatory / irritative diseases such as arthritis. However, these drugs have some undesirable side effects when used for prolonged periods; the most important of these are irritation of the gastrointestinal tract and the development of ulcers, which are still an unresolved medical problem.

For the most potent non-steroidal analgesics / anti-inflammatory drugs, which are derivatives of aryl acetic acid or aryl propionic acid, it has been observed that the ratio of therapeutic and undesirable side effects after subcutaneous and oral administration (which is more convenient for patients) same. These side effects were not expected to be dependent on the substance being in direct contact with the gastrointestinal cells in soluble concentrated or solid form; rather, the plasma level of the active ingredient is decisive [see Lombardino (ed.), Nonsteroidal Antiinflammatory Drugs; Ottemess and Bliven, Chapter 4, 229-230. side]. Therefore, it has been determined that the esters of these analgesic / anti-inflammatory carboxylic acids should not be free from undesirable side effects of the corresponding acids. Indeed, these acids are generally commercially available in free form (e.g., indomethacin, naproxen, ketoprofen, ibuprofen) or in the form of their salts (e.g., diclofenac sodium salt, ketorolactrometamate) but not in the form of their esters; where these compounds are proposed to be used in the form of esters, these esters are quaternary ammonium salts (see, for example, European Patent Application No. 289,262).

Despite many attempts, the need for new non-steroidal analgesic / anti-inflammatory compounds, which have a significant therapeutic effect and are less irritating to the gastrointestinal tract and less likely to cause ulceration, has not yet been met.

The present invention is a pharmaceutically acceptable salt, preferably the oxalate, of a (±) -5-benzoyl-2,3-dihydro-1H-pyrrolizine-1-carboxylic acid 2- (1-pyrrolidinyl) ethyl ester of the formula (I). made available.

It is known that commercially available ketorolac (trometam Last) causes undesirable side effects (gastrointestinal irritation and ulceration). Surprisingly, the use of a compound of the present invention significantly reduces unwanted side effects, making the product a very beneficial analgesic / anti-inflammatory.

The present invention also provides pharmaceutical compositions comprising an effective amount of a pharmaceutically acceptable salt of ketorolac-2- (1-pyrrolidinyl) ethyl ester together with pharmaceutically acceptable excipients, in particular galenical preparations for oral or parenteral administration (tablets, coated tablets, capsules, syrups, suspensions, injectable solutions, etc.).

According to the present invention, a therapeutically effective amount of the product is mixed with an appropriate amount of a pharmaceutically acceptable excipient.

The 2- (1-pyrrolidinyl) ethyl ester of ketorolac is prepared by reacting (±) -5-benzoyl-2,3-dihydro-1H-pyrrolizine-1-carboxylic acid with 2- (1-pyrrolidinyl) ethyl-. alkylation with chloride or an equivalent alkylating agent and, if desired, addition of the appropriate acid to the desired addition salt which is isolated by crystallization.

Comparative studies in Table 1 show that the therapeutic effect of the oxalic acid salt of the 2- (1-pyrrolidinyl) ethyl ester of ketorolac (Table B) is similar to that of the trometamate ketorolac (Table A) in commercially available formulations. We were used. It is surprising in the prior art that the two products have similar analgesic / anti-inflammatory and antipyretic properties.

Even more surprisingly, the comparative experimental results shown in Table 2 show that the oxalic acid salt of the 2- (1-pyrrolidinyl) ethyl ester of ketorolac (column B) exhibits significantly less adverse side effects than the trometamol salt of ketorolac (column A). It has been observed that the ulcer index for (B) is only one-third as that for (A); in studies of potential damage to gastric tissue, all animals treated with (B) remained unchanged, while all animals treated with (A) showed bleeding and necrosis; and the gastric mucosa is also significantly less (B) than (A). And this is coupled with an acceptable acute toxicity for both (A) and (B). The 2- (1-pyrrolidinyl) ethyl ester of ketorolac is therefore potentially more pharmacologically advantageous than ketorolac.

There is no indication in the prior art that the surprisingly low level of adverse side effects is attributable to the 2- (1-pyrrolidinyl) ethyl ester of ketorolac. This level is more or less due to the presence of a 5-membered pyrrolidine ring, the importance of which is illustrated below.

When the same number of carbon atoms (two additional hydrogen atoms) is present but in the open form instead of the pyrrolidine ring, the therapeutic effect remains virtually the same, but the benefit of unwanted side effects disappears. This can be seen from the results in column (C) of Tables 1 and 2 obtained in comparative experiments with the maleate salt of ketorolac-2- (diethylamino) ethyl ester. According to the table, the ulcer index of 2- (diethylamino) ethyl ester is twice as high as that of 2- (1-pyrrolidinyl) ethyl ester, and the risk of gastric mucosal damage is much greater than that of the latter. It is virtually identical to the result of the test with trometam Last. A similar effect can be observed when methyl groups are substituted for ethyl groups, i.e. experiment2

2-dimethylaminoethyl ester (not shown in the table) is used.

When replacing the 5-membered pyrrolidine ring with a 6-membered ring, no advantage is obtained when testing the 2- (1-piperidinyl) ethyl ester (not shown in the table) or the corresponding 2- (4-morpholinyl) ethyl ester.

The high potency of the 2- (1-pyrrolidinyl) ethyl ester of ketorolac and its pharmaceutically acceptable salts relative to the ketorolac and other structurally related esters (prepared for the first time) and the low level of undesirable side effects make the product of the present invention a particularly useful analgesic. makes it an anti-inflammatory agent.

The invention is illustrated by the following examples.

Example 1

Comparative studies on the therapeutic effect

Table 1 shows the results of a comparative analgesic / anti-inflammatory and antipyretic effect of ketorolac (commercially available) tromethamate (A), ketorolac 2- (lpyrrolidinyl) ethyl ester oxalate (subject of the present invention). ) and after oral administration of ketorolac-2- (diethylamino) ethyl ester maleate (Comparative C) was obtained in rats.

The analgesic effect was measured by assaying for inhibition of distortion induced by the peritoneal administration of 0.1 ml of 3% acetic acid [Köster, R., Anderson, M., De Beer, E., J. Fed. Proc., 18, 412 (1959)].

The antiinflammatory activity was evaluated using the rat foot edema method using 1% carrageenan and measuring the% reduction in rat foot volume increase (Winter, C.A., Risley, E.A. and Nuss, G.W. Proc. Soc Exp Bioi. Med., 111: 544-547. (1962)].

The antipyretic effect was determined by inducing an increase in the body temperature of the rat with 20% brewer's yeast and measuring the rectal temperature of the rat 5, 6, 7 and 8 hours later (Colot, M., "Notions Techniques de Pharmacologie générale", ed. Masson, 1972.). The percentage increase was determined relative to the comparative example.

Example 2

Comparative studies on adverse reactions

Table 2 shows the results of a comparative study of acute toxicity, ulcerative activity, potential damage to gastric tissue and gastric mucosa, which was obtained in a rat study with (commercially available) ketorolacetrometham, ketorolac-2- (1-pyrrolidinyl) according to the invention. ester oxalate salt and ketorolac-2 (diethylamino) ethyl ester maleate (here comparative formulation). Acute toxicity was expressed as LD _{5 ()} and was comparable and acceptable in the three cases.

Three groups of 6-6 rats were used to investigate the ulcer effect. The three products mentioned above were administered orally at 62.5, 100 and 100 mg / kg. The ulcer effect was evaluated macroscopically with an ulcer index by the method of Schriver, DA et al., 1975, "The Profile of the Rat Gastrointestinal Toxicants Used to Treat Inflammatory Diseases", Tox. Appl. Pharmacol. where the index is equal to the sum of the scores for each animal multiplied by the number of animals above zero divided by the number of all animals (0 = normal; 1 = slight bleeding; 2 = notable bleeding; 3 = small ulcer; 4 = large, 2 mm 5 = perforated ulcer, Chaumontet, M., et al., Comparative study of two antiulcerative drugs (Glaziovine & Sulpiride, Arz. Forsch. Drug Rés., 28 (11), 11, 1978).

In the same animals, the extent of the probability of gastric tissue damage was examined by microscopic determination of the extent of the various degrees of injury: unchanged, bleeding, wound.

Gastric mucosal damage was determined from the gastric mucosal content as a cell protective factor in animals treated with Compound A or B or once at 100 mg / kg p. She. or 25 mg / kg / day p. She. administration for 7 days. Three groups of 6-6 rats were used for each experiment. One group was the comparator and the result was expressed as a% reduction in this group.

Table 1

Comparison of the effects of three ketorolac derivatives: (A) trometam last; (B) 2- (1-Pyrrolidyl) ethyl ester oxalate; (C) 2- (diethylamino) ethyl ester maleate Property (see text) (THE) (B) (C) Analgesic effect po ED ₅₀ mg / kg 0.32 0.36 0.35 Anti-inflammatory effect po ED ₅₀ mg / kg > 5 > 5 > 5 Antipyretic effect po ED ₅₀ mg / kg approx. 3 > 3 approx. 3

Table 2

Comparison of side effects of two ketorolac derivatives: (A) trometam last; (Β) 2- (1-pyrrolidinyl) ethyl ester oxalate; (C) 2- (dimethylamino) ethyl ester maleate Property (see text) (THE) (B) (C) Acute toxicity after LD ₅₀ (mg / kg) in mouse LD ₅₀ (mg / kg) rat 118 199 198 235 93 211 Ulceration (100 mg / kg) Index of ulceration (up to 500) 400 (1) 133 263

HU 216 841 Β

Table 2 (continued)

Comparison of the side effect of Kct kctorolac derivative: (A) trometam last; (B) 2- (1-pyrrolidinyl) ethyl ester oxalate; (C) 2- (dimethylamino) ethyl ester malate Property (see text) (THE) (B) (C) Probability of gastric tissue damage (6 rats, microscopic) Animals without change 0 6 1 Animals bleeding 2 0 0 Animals with wounds 4 0 5 Acute gastric mucosal damage (100 mg / kg)% reduction compared to comparator 52 27 (P <0.05) n. s. - Chronic gastric mucosal damage (100 mg / kg)% reduction relative to comparator 31 7 (P <0.05) n. s. - (1) 62.5 mg / kg

Pharmacodynamic ED ₅₀ mg / kg po

quality Citrate Citrate molecule- weight by adjusted oxalate Painkiller effect 0.7 0.56 0.36 Anti-inflammatory effect 6 4.8 > 5 Antipyretic effect 3 2.4 > 5

Toxicity LD ₅₀ mg / kg po

Experiment Citrate Citrate corrected for molecular weight oxalate mouse 116 93 198 rats 263 210 235

Ulcerogenic activity

quality Citrate oxalate Equivalent dose (mg / kg p. 0.) Value Dose (mg / kg p. 0.) Value Ulcer index 80 52 100 133 Microscopic injury 80 2/10 100 0/6

quality Citrate oxalate Equivalent dose (mg / kg p. 0.) Value Dose (Mg / kg po) Value Acute damage to the gastric mucosa 80 2 100 27 Chronic damage to the gastric mucosa 20 0 25 7

Example 3

Production of products

For the preparation of ketorolac-2- (1-pyrrolidinyl) ethyl ester, (±) -5-benzoyl-2,3-dihydro-1H-pyrrolizine-1-carboxylic acid (ketorolac) (2.55 g, 10 mmol) and 4, 2 g of sodium carbonate are refluxed for about 30 minutes. 2- (1-Pyrrolidinyl) ethyl chloride hydrochloride (2.00 g, 15 mmol) was added and reflux continued for 15 hours. The reaction mixture was then concentrated by removing the solvent under reduced pressure. The residue was slurried in dichloromethane and washed several times with saturated aqueous sodium chloride. The organic phase is dried over sodium sulfate, filtered and the solvent is removed by vacuum distillation. The oil was dissolved in absolute ethanol and 1.26 g of anhydrous oxalic acid were added in small portions. Ketorolac-2- (1-pyrrolidinyl) ethyl ester oxalate, 1: 1, was obtained in 82% yield. After recrystallization from ethanol, m.p. 167-169 ° C.

In a similar procedure, reacting 2- (diethylamino) ethyl chloride hydrochloride with 2- (1-pyrrolidinyl) ethyl chloride hydrochloride and maleic acid instead of oxalic acid afforded ketorolac-2- (diethyl) in 84% yield. amino) ethyl ester maleate. After crystallization from acetone, the compound has a melting point of 90-92 ° C.

Claims (6)

A process for the preparation of pharmaceutically acceptable addition salts of (±) -5-benzoyl-2,3-dihydro-1H-pyrrolizine-1-carboxylic acid 2- (1-pyrrolidinyl) ethyl ester of formula (I), characterized in that: ±) -5-Benzoyl-2,3-dihydro-1H-pyrrolizine-1-carboxylic acid is alkylated with 2- (1-pyrrolidinyl) ethyl chloride or its salt or equivalent alkylating agent and the appropriate acid is added to form the desired addition salt. Process according to claim 1, characterized in that the appropriate acid to form the desired addition salt is oxalic acid. 3. A process for the preparation of a pharmaceutical composition comprising (±) -5-benzoyl-2,3-dihydro-1H-4 (I) according to claim 1 or 2. The pharmaceutically effective amount of the addition salt of pyrrolizine-1-carboxylic acid 2- (1-pyrrolidinyl) ethyl ester is added to the desired amount of one or more suitable and pharmaceutically acceptable excipients. 4. A process according to claim 3 wherein the (±) -5-benzoyl-2,3-dihydro-1H-pyrrolizine-1-carboxylic acid 2- (1-pyrrolidinyl) -ethyl- The oxalate salt is used as the addition salt of the ester. 5. The method of claim 3 or 4, wherein the one or more pharmaceutically acceptable excipients are formulated as a galenic composition for oral or parenteral administration. 5 6. The method of claim 3 or 4, wherein the pharmaceutical composition is for treating pain or inflammation in humans or animals.